119: G-quadruplexes, pericentromeres, and B cell genome instability

Waisertreiger I et al., PNAS - This study tests how stabilization of G-quadruplex (G4) DNA by ligands such as pyridostatin (PDS) affects genome stability in primary and malignant B cells. The authors map PDS-induced chromosomal breaks and fusions to ribosomal DNA (rDNA) and pericentromeric major satellite (MaSat) repeats and link G4 stabilization to tetraploidization in cells lacking G2/M arrest. Key terms: G-quadruplex, pyridostatin, pericentromeric, ribosomal DNA, tetraploidy.

Study Highlights:
Pyridostatin (PDS) treatment induces recurrent DNA breaks and chromosome fusions localized mainly to rDNA arrays and pericentromeric MaSat repeats in mouse primary B cells and B cell lymphoma lines. PDS causes high levels of tetraploid metaphases in primary mouse B cells (and in GM12878 cells) that correlate with abundant dicentric chromosomes and absence of a WEE1-dependent G2/M arrest, whereas CH12 cells arrest in G2/M and largely avoid tetraploid metaphases. Similar pericentromeric fragility is seen with the G4 ligand CX-5461 and in human lymphoma cell lines, supporting a role for G4 stabilization in driving pericentromeric instability.

Conclusion:
G4-stabilizing ligands provoke replication-associated breaks at rDNA and pericentromeric repeats, producing dicentric fusions and, when checkpoint arrest is absent, tetraploidization; this identifies both a vulnerability in B cell cancers and a potential therapeutic avenue with caution for off-target tetraploidization.

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Article title:
G- quadruplex stabilization induces DNA breaks in pericentromeric repetitive DNA sequences in B lymphocytes

First author:
Waisertreiger I

Journal:
PNAS

DOI:
10.1073/pnas.2506939122

Reference:
Waisertreiger I., Ayelea K., Elshaikha M.H., Barlow J.H. PNAS (2025) doi:10.1073/pnas.2506939122

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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Episode link: https://basebybase.com/episodes/gquadruplex-stabilization-triggers-pericentromeric-dna-breaks-in-b-cells

QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-08-27.

QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Substantive audit of mechanistic and experimental results: G4 stabilization by PDS, localization of breaks to rDNA and pericentromeric MaSat repeats, tetraploidy in mouse primary B cells and GM12878, absence of tetraploidy in CH12 due to G2/M arrest (and its reversal by inhibitors), human B cell lines (GM12878 and Raji
- transcript topics: G-quadruplex structures and PDS mechanism; PDS-induced chromosomal breaks at rDNA and MaSat repeats; tetraploidy and cell-cycle checkpoint differences across cell types; CH12 cells: G2/M arrest, CDK1 inhibition, WEE1 interplay; human B cell lines GM12878 and Raji; PBMC safety; therapeutic implications, drug combinations, and safety considerations

QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 5
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- PDS stabilizes G-quadruplexes and locks them, hindering helicase unwinding and triggering replication-associated DNA breaks
- PDS-induced damage localizes predominantly to rDNA repeats and pericentromeric MaSat repeats in mouse primary B cells
- Tetraploidy is observed in mouse primary B cells and in GM12878 human B cells after PDS treatment; CH12 cells display G2/M arrest preventing tetraploidy
- Healthy PBMCs show little to no chromosomal instability under PDS exposure, indicating a therapeutic window
- CX-5461 and Phen-DC3 also drive pericentromeric damage, supporting a G4-stabilization mechanism; WEE1 inhibition can modulate G2/M arrest and tetraploidy
- Combination strategies (e.g., PDS with WEE1 inhibitors) enhance chromosomal instability in CH12 cells, suggesting potential synergy

QC result: Pass.